Selective mtDNA mutation accumulation results in β-cell apoptosis and diabetes development

Kenneth G. Bensch, Justin L. Mott, Shin Wen Chang, Polly A. Hansen, Michael A. Moxley, Kari T. Chambers, Wieke De Graaf, H. Peter Zassenhaus, John A. Corbett

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

To test the hypothesis that somatic mitochondrial (mt)DNA mutation accumulation predisposes mice to β-cell loss and diabetes development, transgenic mice expressing a proofreading-deficient mtDNA polymerase-γ under the control of the rat insulin-1 promoter were generated. At 6 wk of age, mtDNA mutations reached 0.01% (1.05 mutations/10,000 bp) in islets isolated from transgenic mice. This mutational burden is associated with impaired glucose tolerance and a diabetes prevalence of 52% in male transgenic mice. Female transgenic mice maintain slightly elevated fasting glucose levels, mild glucose intolerance, and a diabetes prevalence of 14%. Diabetes in transgenic animals is associated with insulin insufficiency that results from a significant reduction in β-cell mass. Importantly, apoptosis of β-cells is increased 7-fold in female and 11-fold in male transgenic mice compared with littermate controls. These results are consistent with a causative role of somatic mtDNA mutation accumulation in the loss of β-cell mass and diabetes development.

Original languageEnglish (US)
Pages (from-to)E672-E680
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume296
Issue number4
DOIs
StatePublished - Apr 2009

Keywords

  • Insulin
  • Islet
  • Mitochondrial deoxyribonucleic acid

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Bensch, K. G., Mott, J. L., Chang, S. W., Hansen, P. A., Moxley, M. A., Chambers, K. T., De Graaf, W., Zassenhaus, H. P., & Corbett, J. A. (2009). Selective mtDNA mutation accumulation results in β-cell apoptosis and diabetes development. American Journal of Physiology - Endocrinology and Metabolism, 296(4), E672-E680. https://doi.org/10.1152/ajpendo.90839.2008